Natural killer cells are generally viewed as a first line of defense in cancer immunosurveillance and are critical players in immune-mediated cancer rejection. We have recently described a new subset of unconventional NK cells that reside in mucosal tissues and are characterized by production of large amounts of IL-22. We refer to this novel cell subset as NK-22. Although the origin of these cells is still unclear and their relationship to conventional NK cells a matter of debate, we and others have shown that these cells can acquire features typical of conventional NK cells when exposed to inflammatory cytokines. Moreover, recent work has suggested that a similar cell type plays a critical role in initiating tumor rejection. Our preliminary data show that NK-22 are highly dependent on the transcription factor aryl hydrocarbon receptor (AHR) for their development. AHR is known to bind dietary compounds such as indol-3-carbinol (I3C) and flavonoids that are associated with anti-tumor activity. We hypothesize that by engaging AHR through dietary supplements, we can manipulate the numbers and or the activity of NK-22. In Specific Aim 1 we will test the effect of I3C and the flavonoid quercetin on NK-22 expansion and function in vivo. In Specific Aim 2 we will determine whether these supplements impact the anti-tumor function of NK-22 in spontaneous and transplantable tumor models. We discovered NK-22, contributed to the initial characterization of their development and function and have generated unique NK-22 specific reagents as well as mouse strains lacking NK-22 or AHR in several immune and non-immune cell types. Therefore, we are in a unique position to directly test the impact of specific dietary supplements allegedly associated with anti-cancer activity on tumor surveillance by innate immune cells. !